The goal of this proposal is to understand why people with diabetes develop a more rapid build-up of plaque in arteries. This problem is commonly called ?atherosclerosis? and it is directly responsible for several types of serious cardiovascular diseases that cause numerous disabilities and premature death. A major reason why diabetic individuals develop severe atherosclerosis early on in life is because of high blood sugar that is also called ?hyperglycemia?. Exactly why hyperglycemia enhances atherosclerosis is not known. Unfortunately, studies of diabetic mice in which hyperglycemia accelerates atherosclerosis also led to increased blood cholesterol levels. Because such added blood cholesterol can itself accelerate atherosclerosis, and because diabetic humans do not always have increased blood cholesterol, how hyperglycemia causes more severe atherosclerosis remains incompletely understood. Work performed in our laboratory led to a new strain of genetically engineered mice in which diabetic hyperglycemia does not further increase blood cholesterol levels. Our latest studies of these diabetic mice reveal that hyperglycemia accelerates atherosclerosis by increasing the number of activated immune cells that accumulate in the blood and the artery wall. We also uncovered that hyperglycemia alters the expression of a class of intracellular molecules called microRNA that can regulate genetic programs in immune cells making them more active and prone to cause inflammation. Because an activated immune system is known to accelerate atherosclerosis, our findings could in part explain clinical observations of accelerated and aggressive forms of atherosclerosis among diabetic individuals. Therefore, the central focus of our grant proposal will be to uncover how hyperglycemia acts to alter microRNA levels in immune cells and their progenitors to drive their activation and thereby accelerate atherosclerosis. In our First Aim we will define which microRNA are altered in immune cells and their progenitors in the blood, spleen and atherosclerotic lesions of diabetic mice, and how this alters their cellular activation. We will study immune cells exposed to high levels of glucose to test if increased cellular oxidative stress is responsible for reducing microRNA levels. We will also identify which enzymes are responsible for these effects. In our Second Aim we will test if increasing an anti-oxidant activity in immune cells can overcome effects of hyperglycemia to maintain normal microRNA levels and thereby prevent immune cell activation and atherosclerosis in diabetic mice. We will also test if a forced expression of select microRNA in immune cells can overcome effects of hyperglycemia to reduce inflammation and atherosclerosis in diabetic mice. We will also test if these approaches can be combined with glucose lowering to control diabetic atherosclerosis. Our findings could provide much needed new treatments to diabetic individuals and those yet to develop diabetes based on the manipulation and use of microRNA to control diabetic atherosclerosis that remains a major cause of serious cardiovascular diseases despite widely available therapies that reduce blood glucose and lipids.